Uracil thioureas for reviving an animal given an overdose of barbiturate

ABSTRACT

URACIL THIOUREAS HAVING THE GENREAL FORMULA   2-(X=),4-(O=),1,3-DI(CH3-),6-(R-NH-C(=S)-NH-)-1,2,3,4-   TETRAHYDROPYRIMIDINE   WHEREIN X IS SELECTED FROM THE GROUP CONSISTING OF O AND S, AND WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL HAVING FROM 1 TO ABOUT 4 CARBON ATOMS, ALLYL, METHALLYL AND PHENYL, FOR EXAMPLE, 1-(2-DIKETO1,3 - DIMETHYL-1,2,3,4-TETRAHYDROPYRIMIDIN-6-YL)-3-METHYL2-THIOUREA, ARE PHARMACEUTICALLY ADMINSITERED TO ANIMALS GIVEN AN OVERDOSE OF BARBITURATE FOR REVIVING SAID ANIMALS.

United States Patent 3,749,783 URAClL THIOUREAS FOR REVIVING AN ANIMALGIVEN AN OVERDOSE 0F BARBITURATE Arthur Berger, Skokie, 11]., andEdeltraut E. Borgaes,

Sindelfingen, Germany, assignors to Baxter Laboratories, Inc., MortonGrove, Ill.

No Drawing. Original application Aug. 13, 1969, Ser. No. 849,890, nowabandoned. Divided and this application Dec. 6, 1971, Ser. No. 205,281

Int. Cl. A61k 27/00 US. Cl. 424-251 1 Claim ABSTRACT OF THE DISCLOSUREUracil thioureas having the general formula wherein X is selected fromthe group consisting of O and S, and wherein R is selected from thegroup consisting of lower alkyl having from 1 to about 4 carbon atoms,allyl, methallyl and phenyl, for example, 1-(2,4-diketo- 1,3dimethyl-1,2,3,4-tetrahydropyrimidin-6-yl)-3-methyl- Z-thiourea, arepharmaceutically administered to animals given an overdose ofbarbiturate for reviving said animals.

This is a divisional of application Ser. No. 849,890, filed Aug. 13,1969, now abandoned.

The present invention relates to novel organic uracil thioureas. Moreparticularly, this invention relates to ring substituted uracilthioureas having the general formula:

CHa-N wherein X is selected from the group consisting of O and S, andwherein R is selected from the group consisting of lower alkyl havingfrom 1 to about 4 carbon atoms, allyl, methallyl and phenyl.

The compounds of the present invention have been found to have potentcentral nervous system anti-depressant activity in animals. The abilityof these compounds to revive animals given large doses of barbiturateshave been shown in mice, rabbits and dogs. As such, the compounds of thepresent invention are useful agents for these and other animals asnarcotic, barbiturate and anesthetic antagonists and as psychomotor andrespiratory stimulants. These compounds are new compounds which have notbeen described heretofore in the literature and have unique barbiturateantagonist properties.

Certain S-substituted positional isomers of the present compounds havebeen described heretofore as having cytostatic properties by Kumar,German Pat. 1,219,489. However, the S-substituted uracil thioureas werefound to be inactive central nervous system anti-depressants.

The synthesis of the novel uracil thioureas of the present invention canbe eliected by reacting 6-amino-l,3-dimethyluracil or6-amino-l,3-dimethyl-2-thiouracil with an appropriate isothiocyanate.This synthesis is facilitated by reaction in the presence of a mutualsolvent such as an amide, for example, dimethylformamide, or asulfoxide, for example, dimethylsulfoxide.

C--NHCSNHR 31,749,783 Patented July 31, 1973 ice wherein X and R are aspreviously defined.

Illustrative of the isothiocyanates which can be used in the abovereaction are the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,allyl, methallyl and phenyl isothiocyanates and the like. Theisothiocyanate reagents are generally available commercially or can bemade by conventional procedures, for example, by reaction of an amine,CS and NaOH as described in Organic Syntheses, Coll. vol. III, p. 599(1955), John Wiley & Sons, Inc., New York and London.

The compound 6-amino-1,3-dimethyluracil also is generally availablecommercially or can be made by conventional procedures, for example, byreaction of 1,3-dimethylurea with ethyl cyanoacetate as described byTraube, Ann., vol. 432, p. 281 (1923).

The corresponding 6-amino-l,3-dimethyl-2-thiouracil can also be made byconventional procedures, for example, by reaction of NN-dimethylthioureawith cyanoacetic acid in acetic anhydride and acetic acid as describedby Wooldridge and Stack, J. Chem. Socy 1962, pp. 1863-8 at 1865, and bySpeer and Raymond, J. Am. Chem. Socy, vol. 75, pp. 1141l5 (1953).

Although specific methods of preparation of the novel uracil thioureasof the present invention are described herein, it will be understoodthat these compounds are not limited to these specific methods ofpreparation. For example, an alternative method of preparation consistsof meth'ylating the ring unsubstituted uracil thiourea. Other methods ofpreparation of these compounds can be devised by those skilled in theart.

The novel compounds of the present invention have been administered bothintravenously (-i.v.) and intraperitoneally (i.p.) in suspensions ofpectin and gum acacia solutions and in alcohol-water solutions. Theseroutes of administration as well as the oral route of administration canbe used. Other methods of administration will be apparent to thoseskilled in the art.

Elfective barbiturate antagonist dosages can range from about one to1,000 mg. per kg. of body weight and can take the form of tablets,powders, capsules, elixers and the like dosage forms in admixture withcommon solid and liquid diluents, carriers and adjuvants such as, forexample, cornstarch, lactose, talc, stearic acid, magnesium stearate,gelatin, acacia and locust bean gums, alcohol, water, vegetable oils andthe like materials. Other effective dosages of the novel compounds canbe determined by reference to the specific examples set forthhereinafter. It has been unexpectedly found that high dosages of thesecompounds lose their toxicity in the presence of the active barbituratesand thus appear to be less toxic in the pres ence than in the absence ofbarbiturates.

The following examples will further illustrate the present inventionalthough the invention is not limited to these specific examples. Allpercentages and parts herein are on a weight basis unless otherwisespecified.

EXAMPLE I Synthesis of1-(2,4-diketo-1,3-dimethyll,2,3,4-tetrahydropyrimidin-6-yl)-3-methyl-2-thiourea A mixture of 31.0 grams (0.20 mole) of 6-amino-l,3-dimethyluracil and 20.0 grams (0.27 mole) of methyl isothiocyanate in400 ml. of dimethylformamide was heated under reflux for two hours afterthe reaction mixture had become clear for a total reaction time of 2.5to 3 hours. The mixture was allowed to cool to about room temperatureand then poured into chopped ice. The precipitate was collected andrecrystallized from methanol with decolorizing carbon treatment. Theyield was 31.1 grams (68% f the theoretical) of light yellow crystals of1-(2,4-diketo-1,3-dimethyl 1,2,3,4tetrahydropyrimidin-6-yl)-3-methyl-2-thiourea, M.P. 2301 C.

EXAMPLE II Synthesis of 1-n-butyl-3-(2,4-diketo-1,3-dimethyl-1,2,3,4-tetrahydropyrimidin-6-yl -2-thiourea A mixture of 31.0 grams (0.2 mole)of 6-amino-1,3- dimethyluracil and 30 ml. (excess) of butylisothiocyanate in 400 ml. of dimethylformamide was heated at just belowthe reflux temperature for 1.5 hours. The reaction mixture was cooled toabout 50 C. and then poured into crushed ice. A light yellow precipitateformed immediately, was collected on a filter and crystallized frommethanol. The light yellow crystals of1-butyl-3-(2,4-diketo-1,3-dimethyll,2,3,4-tetrahydropyrimidin-6-yl)-2-thiourea,M.P. 133-4 C., weighed 42.6 grams (78.8% of the theoretical) afterdrying.

Other examples of the uracil thioureas of the present invention weresynthesized according to the procedure of the above examples. Theanalytical data determined for these compounds are set forth in thefollowing table:

a trial dose of the test compound is used as the end point to providethe values given in the tables as the effective BAD (median barbiturateantagonist dose). The margin of safety of the test compound is shown bythe ratio of the LD (median lethal dose) to the effective barbiturateantagonist dose.

In this procedure, the LD s and BAD s were determined by subjecting themice to at least three logarithmically graded doses with ten mice ateach dose level for each compound and calculating according to theprocedure of Miller et 211., Proc. Socy Exper. Biol. and Med., vol. 57,p. 261 (1944). The lethal dose of the barbiturate which was administeredwas the LD (the dose required to kill at least 9 of every 10 mice), or126 mg./kilo of body weight.

TABLE II.-BARBITURATE ANTAGONIST DATA ON URAOIL THIO UREAS, MGJKG. INMICE E X=C (ll-NEG SNHR CHqN CH LD BAD LD X equals R equals BAD f 'lhreeanimals tested at each dose.

TABLE L-ANALYTICAL DATA ON URACIL THIOUREAS r N NIIG S NHR 5 r CHAN CHAnalysis, percent Melting Calculated Found point, Empirical X equals Requals C. formula C H N S C H N S CKHiZNiOIS 42. 09 5. 3O 5. 33CDHHN4OZS 44. 61 5. 82 5. 81 C 0H 4N4O 18 47. 23 5. 55 5. 67OIOI'IHN402S 44. 42 5. 22 5. 64 O1OHMN4OZS 46. 8G 6. 29 6. 20 CoH15N4OzS 40. 86 6. 29 6. 27 cuHieNtozs 49. 23 6. 01 0. 14 C11I'I13N4O2S48. 87 6. 71 6. 85 CllHlBNtOZS 48. 37 6. 71 6. 64 C iH14N4O 18 53. 78 4.86 4.82

Th desirable central nervous system anti-depressant properties of theuracil thiourea of this invention are illustrated by the activity ofthese compounds in protecting mice against lethal doses of pentobarbitalsodium (barbiturate antagonist activity). These illustrative results areshown in the following Tables 11 and III in which the compounds of thepresent invention are compared with seven reference central nervoussystem anti-depressants. In this comparison, which is a modification ofthe procedure reported by Kimura and Richards, Arch. Intern.Pharmacodyn., vol. 110, pp. 29-42 (1957), the ability of the testcompound to reverse a lethal dose of barbiturate is determined. The lifeor death of the test animals following administration of a lethal doseof the barbiturate and then TABLE IIL-REFERENCE CNS ANTI-DEPRESSANTS,MG./ KG. IN MICE From the results shown in the above tables it can beseen that five of the compounds of the present invention are more activethan the seven reference compounds. Most importantly, the safety marginsof eight of the novel co1npounds of the present invention are betterthan any of the reference compounds and six have safety margins greaterthan 10.

Various modifications, adaptations and further examples of the presentinvention can be devised, after reading the foregoing specification andthe claims appended hereto, by the person skilled in the art withoutdeparting from the spirit and scope of the invention. Thus, it will beapparent that various mutual solvents other than dimethylformamide anddimethylsulfoxide can be used for the reaction of6-amino-1,3-dirnethyluracil with isothiocyanate to prepare the noveluracil thioureas of the present invention and various methods ofpurification of these novel compounds other than recrystallization frommethanol will be apparent to those skilled in the art. So also, thereaction conditions of temperature, time and proportions of reactantscan be modified from those illustrated in the specific examples. Whensolvent media is used for the synthesis of the uracil thioureas, it ispreferred to use dimethylformamide at reflux temperature. Whendimethylsulfoxide is used as solvent media, it is important to use areaction temperature not above about 150 C., since at substantiallyhigher temperatures this solvent will act as an oxidizing agent toproduce the aforementioned thiazolopyrimidines instead of the hereindesired uracil thioureas. In this synthesis the6-amino-1,3-dimethyluracil or 6-arnino- 1,3-dimethylthiouracil isgenerally reacted with about a molar equivalent or an excess of theisothiocyanate at reflux temperatures. An effective barbiturateantagonist dose of the uracil thioureas can be formulated in anyconventional dosage form for administration, including admixtures withmany solid and liquid diluents, carriers and adjuvants other than thosepreviously described. These dosages can be administered to reviveanimals given an wherein X is selected from the group consisting of Oand S, and wherein R is selected from the group consisting of loweralkyl having from 1 to about 4 carbon atoms, allyl, methallyl andphenyl.

NHOSNHR References Cited UNITED STATES PATENTS 3,105,077 9/ 1963 Mulleret a1 260-2564 FOREIGN PATENTS 1,219,489 6/ 1966 Germany.

OTHER REFERENCES Wagner et al., Synthetic Organic Chemistry, 1953, pp.645, 827-828.

JEROME D. GOLDBERG, Primary Examiner

